Drug induced liver injury is the most common reason for withdrawal of a drug from the market place and it is the most common identifiable cause of acute liver failure. There are interindividual differences in sensitivity to the hepatotoxic effects of drugs, which may be due to the failure to have normal compensatory responses to injury (herein termed adaptive responses) that result in increased susceptibility to liver injury from drugs. The short term goal of this proposal is to determine adaptive responses to drug induced liver injury using acetaminophen as a model. The long term objective is to develop better tests that identify individuals who are susceptible to liver injury from drugs. Studies in rats indicate that acetaminophen hepatotoxicity is associated with differential gene expression in liver in oxidative stress response pathways, energy producing and energy consuming pathways (herein termed the "APAP signature"), which is accompanied by parallel changes in gene expression in whole blood. A preliminary study in healthy volunteers suggests that the "APAP signature" occurs in human whole blood after a single dose of acetaminophen. We hypothesize that the APAP signature is part of the normal adaptive response. The specific aims of this proposal are to determine: 1) if adaptive responses are seen in whole blood, expressed as the APAP signature, 2) if subjects who develop acetaminophen associated liver test elevations fail to adapt. 3) if adaptation occurs in subjects who previously developed liver test elevations with acetaminophen and are retreated. The next step would be to investigate if adaptive responses identified in this proposal are associated with idiosyncratic drug induced liver injury. Dr. Russo's training plan capitalizes on strong established ties with scientists at the National Center for Toxicogenomics and as a coinvestigator in the Drug Induced Liver Injury Network. The genomics training acquired by Dr. Russo will help him transition from an investigator in liver transplantation to a translational researcher in drug induced liver injury.